treatment of congenital vascular malformations using sirolimus: improving quality of life

Conditions: Vascular Malformations

Summary: congenital vascular anomalies are uncommon and belong to the group of rare diseases.these vascular malformations can cause serious complications including obstruction of vital organs and their function, recurrent infection and significantly reduced quality of life of persons affected.treatment options range from conservative to surgical extirpation or intralesional embolisation/sclerosis. unfortunately, this is often not enough. many patients still have complaints like severe pain and invalidation due to the lymphatic or venous malformation making a normal functional life impossible. recent case reports mention the positive effects of refractory patients with sirolimus. sirolimus, also known as rapamycin, is currently the only fda-approved mammalian target of rapamycin (mtor) inhibitor.

congenital vascular anomalies are uncommon and belong to the group of rare diseases. in 1996, the international society of the study of vascular anomalies adopted a new classification, distinguishing vascular malformations from vascular tumors. this classification was revised in 2014 and newly identified genetic features were taken into account. vascular malformations feature dysplastic malformed vessels and are a consequence of a defective development of the embryonic vascular system. vascular malformations can involve lymphatic vessels, capillaries, veins and arteries or even combinations. these vascular malformations are present at birth and grow with the child. treatment options range from conservative to surgical extirpation or intralesional embolisation/sclerosis. unfortunately, this is often not enough. many patients still have complaints like severe pain and invalidation due to the lymphatic or venous malformation making a normal functional life impossible. these vascular malformations can cause serious complications including obstruction of vital organs and their function, recurrent infection and significantly reduced quality of life of persons affected. as the natural course of the disease affects multiple body systems, the therapeutic management is challenging. to date, no other medical treatment options are available. although standard pain medication is given according the (inter) national pain protocols, patients still suffer pain and are not able to function normally in daily life. majority (60-70% percent of the patients) of the patients is not able to have a normal life, with a normal job and normal social activities. children are often not able to go to school normally, cannot play outside and have pain at the site of the malformation. the vast majority of literature reporting medical therapies for vascular anomalies consists of case reports and small series and is complicated by publication bias (negative findings are often not published), inconsistent use of nomenclature, and the absence of clinical trials. recent case reports mention the positive effects of refractory patients with sirolimus. sirolimus, also known as rapamycin, is currently the only fda-approved mammalian target of rapamycin (mtor) inhibitor, indicated for prevention of kidney allograft rejection in adults and children 13 years or older, but is commonly used to manage organ rejection in younger children.

Eligibility criteria:
inclusion criteria: * diagnosis of congenital venous malformation, or lymphatic malformation or combined. * age older than 1 yr. * patients (or legal guardians for children) have to be able to sign the informed consent * patients are either refractory to standard care such as medical treatment (low molecular weight heparins, pain medication etc.), surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications) or there is no possibility for surgical intervention anymore. only patients that have a normal clinical screening (no signs for infection, normal bone marrow function, normal liver and kidney function, normal glucose metabolism etc.) can be included. * patients included have no cardiac impairment * patients have no gastrointestinal impairment as sirolimus is absorbed gastro-intestinal and normal function is needed * no other underlying medical disorder like down syndrome or other syndromes * women of reproductive age have to be informed that contraceptive methods are * mandatory during the study time, pregnant women are excluded * karnofsky score \> 50 exclusion criteria: * no written informed consent * known hypersensitivity to drugs or metabolites from similar classes as study treatment. * patient has other concurrent severe and /or uncontrolled medical condition that would, in the investigator's judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or o2 saturation ≤ 88% at rest, etc.) * recent history of primary malignancy ≤ 5 years * impaired cardiac function or clinically significant cardiac diseases * immunocompromised patients, including known seropositivity for hiv * patient with any other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study. * pregnant or lactating women * karnofsky score \< 50

Keywords: sirolimus mtor inhibitor quality of life mammalian target of rapamycin (mtor)